The FDA's action makes pembrolizumab the first immune checkpoint inhibitor to be approved for the treatment of children with cancer. The drug has previously been approved for the treatment of adult patients with head and neck cancer, melanoma, and lung cancer.

Pembrolizumab received accelerated approval for the new indication based on data from a single-arm clinical trial with more than 200 adult patients. All patients in the trial had cHL that had returned after multiple prior treatments or was no longer responding to treatments that include an autologous stem cell transplantation and/or brentuximab vedotin (Adcetris®). With an accelerated approval, the FDA requires that the drug's manufacturer conduct further studies to confirm the clinical benefit for the indication.

No pediatric patients participated in the clinical trial on which the approval was based. In this instance, the FDA extrapolated the efficacy in pediatric patients from the results that were observed in adults.

This is a bit unusual, said Gregory Reaman, M.D., a pediatric oncologist and associate director for Oncology Sciences in the Office of Hematology and Oncology Products at the FDA. But, he said, the agency has authority "to use extrapolation for efficacy in pediatric patients, particularly in adolescents who have diseases that also occur in the adult population, like cHL."

From a biological standpoint, cHL behaves much the same in adolescents as it does in adults, Dr. Reaman continued, and the course of the disease is similar. "And since the peak age incidence of cHL occurs in adolescence, it really makes sense that pediatric patients should be permitted to have access to this drug for treatment," he said.

In general, checkpoint inhibitors "have demonstrated much less activity in childhood cancers compared to adult cancers," said Brigitte Widemann, M.D., chief of the Pediatric Oncology Branch (POB) in NCI's Center for Cancer Research (CCR). So it's significant that there is some evidence that checkpoint inhibitors may benefit pediatric patients with refractory or relapsed cHL, she said.

The POB is participating in a Children's Oncology Group-coordinated phase I/II trial of two other checkpoint inhibitors in children and young adults with recurrent or refractory solid tumors or sarcomas, she added. The trial is testing nivolumab (Opdivo®) as a single agent or in combination with ipilimumab (Yervoy®).

In the trial that led to the approval, 47% of patients had a partial response and 22% had a complete response. The estimated median duration of response was approximately 11 months.

Some of the most common side effects were fatigue, cough, musculoskeletal pain, diarrhea, and rash. Approximately 5% of patients discontinued treatment due to adverse reactions, and 26% of patients stopped treatment temporarily.

As part of its approval application, Merck, which markets pembrolizumab, submitted safety data on 40 pediatric patients with several cancer types who had been treated with the drug. Side effects these patients experienced were similar to what has been seen in adults, the FDA said, although pediatric patients experienced a higher rate of some adverse reactions, including fatigue and abdominal pain.

The FDA added a warning about the risk of complications of allogeneic hematopoietic stem cell transplantation following treatment with pembrolizumab, advising clinicians to follow patients closely for early evidence of transplant-related complications, including graft-versus-host-disease.

Pembrolizumab is the second checkpoint inhibitor to be approved for adult patients with cHL. In May 2016, the agency granted accelerated approval for nivolumab for patients whose disease has relapsed or worsened after an autologous hematopoietic stem cell transplant followed by brentuximab vedotin.

The approval of a second immunotherapy agent for these patients is a positive development, said Mark Roschewski, M.D., of CCR's Lymphoid Malignancies Branch.

"It's always important to get more options for patients," Dr. Roschewski said, particularly those whose disease is no longer responding to other treatments. In addition, researchers will now be able to test these agents in different ways against a variety of different lymphomas.

"It's important to get more than one drug out there," he said, "because it's really the combinations that will have the biggest impact on patients' lives."

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